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dc.contributor.authorLi, Y.-
dc.contributor.authorNgo, A.-
dc.contributor.authorHoffmann, P.-
dc.contributor.authorFerrante, A.-
dc.contributor.authorHii, C.-
dc.identifier.citationCellular Signalling, 2019; 58:20-33-
dc.description.abstractEndothelial cell injury and death precede atherosclerosis development. Thus, it is important to understand the mechanisms that lead to these early changes in endothelial cells. Although members of the MAP kinase/ERK kinase (MEK) kinase 3 (MEKK3)-MEK5-ERK5 module play an essential role in underpinning endothelial cell survival, how they execute these actions remain poorly understood. Furthermore, there is poor understanding of death-inducing pathways in endothelial cells and it is also unclear whether there are direct interactions between the kinase module and death-inducing pathways. Using immunoprecipitation and liquid chromatography-electrospray ionisation tandem mass spectrometry approaches, we show in human umbilical vein endothelial cells that the MEKK3-MEK5-ERK5 ternary complex contains glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme that can trigger the death of certain cell-types. GAPDH binds directly to MEKK3. Interestingly, serum depletion, a trigger of endothelial cell death, results in a rapid loss of cytosolic MEKK3 and MEKK3-GAPDH interaction. MEKK3 rapidly reappears in the cytosol upon serum replenishment, accompanied by the restoration of MEKK3-GAPDH interaction. During serum starvation or exposure to cytotoxic concentrations of H2O2, GAPDH accumulates in the nucleus. Inhibition of the nuclear accumulation of GAPDH with R-(-)-deprenyl hydrochloride attenuates the degree of cell death. Serum replenishment of serum-starved cells reduces the level of nuclear GAPDH and prevents cell death. Cell-free assays show phosphorylation of GAPDH on four residues by MEKK3. These data not only strongly implicate nuclear GAPDH in causing endothelial cell death but also reveal a potential mechanism for MEKK3 to regulate GAPDH function and hence promote endothelial cell survival.-
dc.description.statementofresponsibilityYong Q. Li, Andy Ngo, Peter Hoffmann, Antonio Ferrante, Charles S. Hii-
dc.rights© 2019 Elsevier Inc. All rights reserved.-
dc.subjectEndothelial cell survival-
dc.subjectMitogen activated protein kinases-
dc.subjectMAP kinase/ERK kinase kinase 3-
dc.subjectGlyceraldehyde-3-phosphate dehydrogenase-
dc.subjectProtein-protein interaction-
dc.titleRegulation of endothelial cell survival and death by the MAP kinase/ERK kinase kinase 3 - glyceraldehyde-3-phosphate dehydrogenase signaling axis-
dc.typeJournal article-
dc.identifier.orcidFerrante, A. [0000-0002-2581-6407]-
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